Most of the mortality and morbidity in patients with cystic fibrosis (CF) results from chronic pulmonary infection with Pseudomonas aeruginosa. Prevention of infection is not currently feasible, primarily because the epidemiology of the infection is not understood. Even basic questions are not known, such as the source(s) of infecting strains, the duration of infection with a strain, and whether infection is transmitted from one patient with CF to another. There is no firm proof that the outcome of patients would improve if infection could be avoided or delayed. However, the occasional report of an adult with CF in good clinical condition and without P. aeruginosa infection, gives rise to hope that infection is not inevitable, and that patients would benefit if infection could be avoided. P. aeruginosa infection occurs in patients without CF only when immunity is compromised, as occurs with burns, cancer chemotherapy, or serious debilitating diseases. When P. aeruginosa infection does occur, the mortality rate is high in comparison to infections caused by other gram negative bacilli. Mortality rates are high despite therapy with new and powerful antimicrobials with enhanced activity against P. aeruginosa. The intrinsic resistance of P. aeruginosa to many antimicrobials is partly responsible, but resistance also develops durng a single course of antimicrobial therapy. This emergence of resistance during therapy is often chromosomally mediated, in contrast to plasmid mediated resistance, which usually does not emerge during a single course of therapy. Long term goals of this project are to develop effective strategies to prevent P. aeruginosa infection in CF patients, and to develop more effective therapy for P. aeruginosa by understanding and overcoming chromosomally mediated resistance. The initial steps toward these goals will be accomplished by: (1) Understanding the natural history of infection with P. aeruginosa in young children with CF by determining the multiplicity of strains infecting individual patients, the duration of infection with a strain, the genetic relationship of isolates cultured from the upper versus the lower respiratory tract, and the frequency of cross-infection, (2) Establishing the frequency of chromosomally mediated resistance to anti-Pseudomonas antibiotics, and (3) Understanding the genetic basis for the emergence of chromosomal resistance by cloning the determinants of resistance and by comparing the alleles for these genes in several resistant and sensitive strains. These aims will be accomplished using a newly described method for strain identification of P. aeruginosa.